Heart Disease in Women: The Cardiac Amyloid Blind Spot That Delays Diagnosis by Years

Transthyretin amyloid cardiomyopathy, a form of heart failure caused by misfolded transthyretin protein accumulating in the heart muscle, has long been framed as a disease of men. A new review in Cardiology and Therapy argues that this framing is itself part of the problem. Drawing together registry data, imaging cohorts and trial enrollment figures, the authors show that women with the condition are diagnosed roughly three years later than men, and in one analysis women under 70 experienced a five-year lag between first symptoms and diagnosis. The delay matters because untreated heart failure from this disease carries a median survival of only about five years, and effective disease-modifying drugs now exist that work best when given early.

The biology of the disease helps explain why it hides in women. Transthyretin is a transport protein made in the liver; when it destabilizes and misfolds, either in its normal wild-type form or in a hereditary variant, it deposits as amyloid fibrils in the myocardium. The resulting stiff or weakened heart can present as heart failure with preserved or reduced ejection fraction, atrial fibrillation, or conduction disease. Large registries report that 60 to 70 percent of patients are male, with some cohorts approaching 90 percent, and a systematic review of 4,669 pooled patients found only 17 percent were women. Yet the review argues that this male predominance likely reflects a combination of biology, referral patterns and historical underdiagnosis rather than a true uniform distribution of disease.

The strongest evidence for under-recognition comes from screening studies that deliberately looked for the disease. In the SCAN-MP study, the largest prospective screening effort for cardiac amyloidosis in Black and Caribbean Hispanic individuals, 5.2 percent of female and 8.2 percent of male participants with heart failure were found to have transthyretin amyloid cardiomyopathy. Although prevalence remained numerically higher in men, the difference did not reach statistical significance. Another recent cohort reached 20 percent female prevalence as awareness and diagnostics improved, and female representation rose with age. In an enriched high-risk cohort of patients with heart failure with preserved ejection fraction and suggestive echocardiographic features, 29 percent were ultimately diagnosed with the disease, underscoring how much amyloid disease hides behind generic heart failure labels.

A central culprit in the diagnostic gap is a single number. Guidelines commonly use a left ventricular wall thickness of at least 12 millimeters as the trigger to pursue amyloid workup, but women with significant myocardial infiltration often fall below that threshold. In a study of 1,062 patients from the French National Reference Centre for Cardiac Amyloidosis, 7 percent of women had an interventricular septum thinner than 12 millimeters compared with 2 percent of men, and the proportion climbed to 15 percent among women aged 77 or younger. In the West German Amyloidosis Center cohort of 240 patients, 20 percent of women versus 3 percent of men missed the cutoff. Reference values themselves differ by sex: one analysis of healthy participants found the range of left ventricular hypertrophy values spanned 10 to 15 millimeters in women versus 12 to 17 millimeters in men using a 95 percent prediction interval, meaning a woman’s diseased heart can look normal against male-derived benchmarks.

Part of the apparent sex difference dissolves when wall thickness is indexed to body size. When septal and posterior wall thicknesses are normalized to body surface area or height, the gap between men and women often attenuates, and some studies even show higher indexed values in women. Women with the disease also tend to have higher ejection fractions and smaller ventricular cavities than men; registry data from THAOS, the largest international amyloidosis registry, showed an average ejection fraction of 53 percent in women versus 48 percent in men and a left ventricular diastolic diameter of 42 versus 46 millimeters. Hormones may shape these phenotypes. Animal models show that dihydrotestosterone upregulates transthyretin transcription more strongly than estradiol, and female patients with increased wall thickness are often post-menopausal and older, suggesting hormonal transitions influence disease onset. In hereditary cohorts, women exhibit less severe cardiac phenotypes on echocardiography, hinting at reduced susceptibility to myocardial infiltration.

Beyond biology, the review points to social forces that systematically delay women’s path to a diagnosis. Among adults over 65, 41 percent of women are widowed compared with 13 percent of men, and many live on incomes below $20,000, circumstances that likely hinder access to advanced imaging and specialized centers. Women are more likely to have symptoms dismissed and to experience delayed specialist referrals, and many serve as caregivers, a role associated with delayed care-seeking. The review also highlights a missed window: the musculoskeletal signatures of amyloidosis, including carpal tunnel syndrome, spinal stenosis and biceps tendon rupture, frequently appear years before cardiac symptoms, offering an early referral opportunity that is often squandered. Notably, most studies find no sex difference in carpal tunnel rates among diagnosed patients, so the warning sign is equally visible if clinicians know to look.

Underrepresentation in research compounds the clinical blind spot. The pivotal treatment trials that established the efficacy of tafamidis and acoramidis each included only 10 percent female patients, the HELIOS-B trial of vutrisiran included 8 percent, and the APOLLO-B trial of patisiran included 11 percent. Trial eligibility criteria themselves excluded women, since every treatment trial required a left ventricular wall thickness of at least 12 millimeters, the very parameter that underdiagnoses them. Staging systems fare no better: the Mayo Clinic staging cohort was 9 percent female, the National Amyloidosis Centre cohorts 15 and 19 percent, and the Columbia system 16 percent, and a risk score built on such a cohort showed lower sensitivity in women than men. Even biomarker response markers may not translate, since women have lower baseline circulating transthyretin concentrations and comprised only 10 percent of the original acoramidis trial population, leaving the sex-specific meaning of treatment-response measures unvalidated.

Outcomes data for women remain frustratingly inconsistent, likely because cohorts are so male-dominated. In the UK National Amyloidosis Centre cohort of 1,732 patients, cardiac phenotypes were largely similar between sexes with no significant mortality differences by genotype. A large French referral-center study found similar five-year survival overall, but younger women fared worse than age-matched men, while other multicenter studies identified male sex as a predictor of worse survival. Treatment access also varies: a study of wild-type disease across 14 European heart centers found lower rates of tafamidis initiation in women, whereas the West German cohort found no difference, with 94 percent of patients receiving stabilizer therapy. On treatment, women maintained higher ejection fractions than men in one cohort but walked slightly shorter distances at one year, and a large study of 1,055 patients on tafamidis found no differences in efficacy or mortality. The review concludes that disease progression on treatment between the sexes remains incompletely characterized.

The path forward, the authors argue, is equally multifaceted. The 2025 American College of Cardiology guidelines are the first to state explicitly that women may not meet the 12-millimeter threshold, a recognition the review hopes will spread. Proposed refinements include indexing wall thickness to body surface area or height, using a left ventricular mass index cutoff of 95 grams per square meter in women, and flagging features such as ejection fraction above 50 percent, septal or posterior wall thickness indexed to height above 9 millimeters per meter, or indexed-to-body-surface-area thickness above 8.5 millimeters per square meter, though the authors stress these criteria come from limited studies and need validation. A prospective screening study of women with heart failure with preserved ejection fraction, modeled on SCAN-MP, could pin down true prevalence. The review also calls for educating primary care providers and orthopedists, since orthopedic manifestations precede cardiac disease by years, alongside community outreach and greater recruitment of women into trials, staging systems and registries so that the next generation of amyloid care is built on evidence that includes half the population it treats.

Subject of Research: Diagnostic delay and under-recognition of transthyretin amyloid cardiomyopathy in women

Article Title: Transthyretin Amyloid Cardiomyopathy in Women: Epidemiology, Diagnostic Delay, and Clinical Implications

Article References: Madhani, A., Ancha, B., Alexander, K. M., & Vaishnav, J. (2026). Transthyretin Amyloid Cardiomyopathy in Women: Epidemiology, Diagnostic Delay, and Clinical Implications. Cardiology and Therapy, 15(3), 463-479. https://doi.org/10.1007/s40119-026-00463-7

Image Credits: AI Generated

DOI: 10.1007/s40119-026-00463-7

Keywords: transthyretin amyloid cardiomyopathy, ATTR-CM, women's heart health, diagnostic delay, cardiac amyloidosis, heart failure, echocardiography, tafamidis, clinical trial representation, social determinants of health, left ventricular wall thickness, sex differences